4-pregnenes and method of preparing the same



United States Patent 2,813,884 Patented Nov. 19, 1957 fiiice 4-PREGNENESAND METHOD OF PREPARING THE SAME Seymour Bernstein, Pearl River, N. Y.,and Ruddy Littell, Rivervale, N. J assignors to American Cyanamid Com-,pany, New York, N. Y., a corporation of Maine No Drawing. ApplicationMay 15, 1956, Serial No. 584,877

17 Claims. (Cl. 260-39745) in which R is a member of the groupconsisting of hydrogen and lower alkanoyl radicals and X is a divalentradical of the group consisting of II CHOH and -C radicals The compoundsof the present invention possess glucocorticoid activity similar tohydrocortisone and are useful as anti-inflammatory agents in arthritic,dermatological, and ophthalmic disorders, and, moreover, are useful inthe treatment of disorders such as asthma, burns, bursitis, and thelike.

The compounds of this invention may be administered to patientssuffering from such disorders as the above orally, in tablets, capsules,etc., parenterally, in suspension or solution, or topically, inointments, creams, or the like.

The compounds of this invention wherein X is the divalent radical CHOH-may be prepared by reacting a 21-loweralkanoyloxy-ZO-ethylenedioxy-16a,17m-dihydroxy-4-pregnene-3-one withdiethyl oxalate in the presence of an alkali metal alkoxide such assodium methylate in a solvent such as tertiary butanol or methanol toform the alkali metal enolate of the correspondingZ-ethoxyoxalyl-4-pregrlene, treating said alkali metal enolate of said2-ethoxyoxalyl-4-pregnene with a methyl halide, such as methyl iodide,under alkaline conditions in a solvent, such as acetone, to form thecorresponding 2a-methyl-2- ethoxyoxalyl-4-pregnene, removing theethoxyoxalyl radical by alkaline hydrolysis of the latter intermediateto give the corresponding 2a-methyl-4-pregnene, and finally removing the20-ethylenedioxy radical by acid hydrolysis.

The 11 fl-hydroxy compounds prepared immediately above may then beconverted to the corresponding ll-oxo compounds by acylating the 1611-and 21-hydroxy groups and then oxidizing with chromium trioxide. By this0 procedure, 16oc,170c,21 trihydroxy-Zwmethyl-4-pregnene- 3,11,20-trionein the form of its 16,21-diacetate was prepared.

The series of reactions to prepare the compounds of the presentinvention can be illustrated by the followlng CH3 CHaOAO CHaOH 0 O o 1 1\0 "-03 ---OH -OH HO OH 0 ONa Alkali metal alkoxide dlethyloxalateMethyl l iodide CH3 CH5 CHZOH CHxOH OH H0 011 0 O OH: Alkalinehydrolysis CIHHOAUJJJJ \O Acld l hydrolysis CH: CH; CH:

CHEOH (iJH OAC CHzOAC ---on ---H ----OH HO OH HO OAC 0* -OAc CH CH 0313on; a j cg: 3

\ Acylation Chromium T" 0: 0: trioxide 0:

The starting material for the methods and products of EXAMPLE 4 thisinvention may be 2l'acetoxy'zo'ethylenedioxy' 1] 16 17 21 -tetr h drox-2 -meth 14- re nene-3 llfl,16a,17a-trihydroxy-4-pregnene-3-one asdescribed and a y g y p g claimed in copending application Serial No.497,473, filed March 28, 1955. Other ketal groups, such as the pro- Am1Xtuf60f5-7 of 20 ethylelledloxy 1 pylene or butylene ketals, may beused in place of ethylene 20 21 tetI'ahYdYOXY y 'l 3 one (from ketal asprotective groups. Also, other acylating agents, such as propionic orbutyric anhydrides, may be used instead of acetic anhydride to block thehydroxylated positions.

The following examples describe in detail the preparation of thecompounds of this invention:

EXAMPLE 1 Sodium enolate of ZO-ethylenedioxy-II5,16 711:,21-tetrahydroxy-Z-ethoxyoxalyl-4-pregnene-3-0ne To 8.0 g. of21-acetoxy-ZO-ethylenedioxy-115,160,17atrihydroxy-4-pregnene-3-onesuspended in 100 ml. of t-butanol was added 3.2 g. of commercial (95%)sodium methylate. To this mixture under nitrogen was added 5 ml. ofdiethyl oxalate, and the mixture was stirred under nitrogen for 6 hours.(Complete solution occurred, and the product precipitated within tenminutes.) Addition of ether, followed by filtration, gave 13 g. ofyellow powder, soluble in water, but insoluble in dilute acid.

EXAMPLE 2 20 ethylenedioxy 11,8,16a,17ot,21 tetrahydroxy 2ethoxyoxalyI-Z-methyl-4-pregnene-3-0ne A mixture of 13 g. of crudesodium enolate of 20- ethylenedioxyl 1l;3,16u,17a,21 tetrahydroxy 2ethoxyoxalyl-4-pregnene-3-one, 13 g. of potassium carbonate, 300 ml. ofacetone, and 50 ml. of methyl iodide was refluxed 20 hours, filteredwhile hot, and the solvent evaporated to a small volume under reducedpressure. Extraction with ethyl acetate, washing with saline, treatmentwith magnesium sulfate and an activated animal charcoal, followed byfiltration and evaporation to dryness under reduced pressure, gave 7.8g. of pale yellow product, which could not be induced to crystallize.

EXAMPLE 3 ZO-ethylenedioxy-l 1 3,1 6 0a,] 701,21-tetrahydroxy-Z-methyl-4-pregnene-3-0ne To 7.8 g. of20-ethylenedioxy-1l;3,l6u,l7ot,21-tetrahydroxy 2 ethoxyoxalyl 2 methyl 4pregnene 3- one (from Example 2) in 250 ml. of absolute methanol wasadded 1.0 g. of sodium methylate (95% purity), and

the mixture was allowed to stand at room temperature for 4 hours. Afterthe addition of a few drops of acetic acid and 20 ml. of water, themethanol was removed under reduced pressure at a temperature notexceeding 35 C. Extraction with ethyl acetate, washing to neutral withsaline, treatment with magnesium sulfate and an activated animalcharcoal, filtration, and evaporation to dryness under reduced pressuregave 5.7 g. of yellow product, which could not be induced tocrystallize.

Example 3), 200 ml. of methanol, and 12 ml. of 8% (v./v.) sulfuric acidwas refluxed for one hour, concentrated under reduced pressure,extracted with ethyl acetate, and washed with sodium bicarbonate,saline, and water. Treatment with magnesium sulfate and an activatedanimal charcoal, filtration, and evaporation under reduced pressure gave4.1 g. of yellow product.

This product was subjected to partition chromatography as follows:

Solvent system-3 ethyl acetate, 2 petroleum ether (boiling point 100C.), 3 methanol, 2. water.

Column 68 cm. length, 5.2 cm. width, hold back volume 780 ml, cuts 20ml. per 10 minutes. Total 250 cuts.

Cuts -200 were combined and evaporated to give 1.4 g. of product. Onecrystallization from acetone-petroleum ether (60-70 C.) gave 700 mg,melting point 193-196 C. A 200 mg. portion was recrystallized twice fromacetone-petroleum ether to give 23 mg., melting point 201- 203 C.Ultraviolet spectrum:

iga-alcohol mp,

The column was washed with methanol and gave 1.17 g. of an oil. Tworecrystallizations fnom acetone gave 70 mg. of crystals which wereidentical with 11fi,16a,l7a,21- tetrahydroxy-4-pregnene-3,20-dione byadmixture melting point and infrared spectral analysis.

EXAMPLE 5 1 6 0:,21 -diacetoxy-1 1B,] 7u-dihydroxy-2a-methyl-4-pregnene-3,20-dione A mixture of l15,160,170:,21-tetrahydroxy-2a-methyl-4-pregnene-3,20-dione (from Example 4) mg.), 3 ml. pyridine, and 0.5 ml.acetic anhydride was heated at about 110 C., for 1 hour. Methanol wasadded and the solvents removed under reduced pressure to a small volume.The residue was washed with cold dilute sulfuric acid, dilute sodiumbicarbonate, then with water to neutrality, treated with magnesiumsulfate and an activated animal charcoal, filtered and evaporated todryness under reduced pressure. The resulting oil was caused tocrystallize by the addition of acetone and petroleum ether to give 70mg, melting point 252-254 C. Two .crystall izations from the samesolvent pair gave 25 mg, melting point 253254 C. Ultraviolet spectrum:

H hfifg 240-241 Ill 1 (e 17, 500 [a], 91.8 (chloroform) EXAMPLE 6 1 60;,21 -d i aceroxy-I 7a-hyd' roxy-2 a-methy l-4-pregene-3 ,1 1

20-tri0ne To a previously prepared and cooled mixture of 180 mg.chromium trioxide in 3 ml. pyridine was added a cooled solution of16u,21-diacetoxy-11,8,17a-dihydroxy- 2a-methyl-4-pregnene-3,20-dione,and the solution was allowed to stand at 20 C. for 18 hours. Methanolwas added and the solvents removed under reduced pressure at about 30 C.The residue was extracted with ethyl acetate, washed with cold dilutesulfuric acid, cold dilute sodium bicarbonate, then water to neutral.The extract was treated with magnesium sulfate and an activated animalcharcoal, filtered and evaporated to dryness under reduced pressure togive a white powder. Three crystallizations from acetone-petroleum ethergave 77 mg., melting point 240.5-241.5 C. Ultraviolet spectrum:

WE 237 m (615,200) Analysis.-Calcd. for C2eH34Os (474.55): C, 65.80;

H, 7.22. Found: C, 65.49; H, 7.30.

We claim: 1. A compound of the group having the general formula (EH20 Ro= |----0H in which R is a member of the group consisting of hydrogenand lower alkanoyl radicals and X is a divalent radical of the groupconsisting of CHOH and C radicals 2. The compound 11 3,16u,17a,21tetrahydroxy 2amethyl-4-pregene-3,20-dione.

3. The compound 16u,21-diacetoxy-11fi,17a-dihydroxy-2a-methyl-4-pregnene-3,ZO-dione.

4. The compound 160:,21 diacetoxy 17a-hydroxy-2umethyl-4-pregnene-3,11,20-trione.

5. A method of preparing compounds having the general formula CHnOR inwhich R is a lower alkanoyl radical, which comprises reacting a 21-loweralkanoyloxy-ZO-ethylenedioxyl1,8,1604,17a-trihydroxy-4-pregnene-3-onewith diethyl oxalate in the presence of an alkali metal alkoxide in asolvent to form an alkali metal enolate of 2-ethoxyoxalylethylenedioxy11fi,16oz,l7oa,21 tetrahydroxy- 4-pregnene-3-one, treating said productwith methyl iodide under alkaline conditions to form 2-ethoxyoxalyl- 20ethylenedioxy 11 3,16oc,l7a,21 tetrahydroxy 2- methyl-4-pregnene-3-one,removing the Z-ethoxyoxalyl radical therefrom under alkaline conditionsto form 20 ethylenedioxy-l 1fi,160t,170t,21 tetrahydroxy 2a methyl- 4pregnene 3 one, subjecting 20 ethylenedioxy-1113,l6a,17a,21-tetrahydroxy-2u-methyl 4 pregnene 3- one to acidhydrolysis to formllfi,16a,l7u,21-tetrahydroXy-Za-methyl-4-pregene-3,ZO-dione, acylatingthe prodnot so formed to yield a 160:,2l-di lower alkanoyloxy-11B,17a-dihydroXy-Za-methyl-4-pregnene3,ZO-dione, and subsequentlyoxidizing said 160:,21-di lower alkanoyloxy-11p,17m-dihydroxy-2a-methyl-4-pregnene-3,ZO-dione to the corresponding3,1 l,20trione.

in which R is a lower alkanoyl radical, which comprises reacting a2l-1ower alkanoyloxy-20-ethylenedioxy-l1 8,-16a,l7a-trihydroxy-4-pregnene-3-one with diethyl oxalate in the presenceof an alkali metal alkoxide in a solvent to form an alkali metal enolateof 2-ethoxy-oxaly1-20 ethylenedioxy-l1B,16a,17a,21-tetrahydroxy 4pregnene- 3-one, treating said product with methyl iodide under alkalineconditions to form2-ethoxyoxalyl-20-ethylenedioxy-l15,160,17a,21-tetrahydroxy 2 methyl 4pregnene-S-one, removing the 2-ethoxyoxalyl radical therefrom underalkaline conditions to form 20-ethylenedioxy-11B,16a,17a,21-tetrahydroxy-2a-methy1- 4 pregnene 3- one, subjecting20-ethylenedioXy-11B,l6a,l7a,2l-tetrahydroxy-2a-methyl-4-pregnene-3oneto acid hydrolysis to form 1 1p,16a,17a,21tetrahydroxy-Zu-methyl-4-pregnene- 3,20-dione, andsubsequently acylating the product so formed to yield a 16a,21-dil0W61alkanoyloxy-11B,17adihydroxy-Zu-methyl-4-pregnene-3,ZO-dione.

7. A method of preparing11fi,16u,l7a,21-tetrahydroxy-Zmethyl-4-pregnene-3,20-dione whichcomprises reacting a 21-lower alkanolyoxy-ZO-ethylenedioxy-11p,-16a,l7a-trihydroxy-4-pregnene-3one with diethyl oxalate in the presenceof an alkali metal alkoxide in a solvent to form an alkali metal enolateof 2-ethoxyoxalyl-20- ethylenedioxy-l1B,l6a,l7a,2l-tetrahydroxy 4pregnene- 3-one, treating said product with methyl iodide under alkalineconditions to form2-ethoxyoxalyl-20-ethylenedioxy-l15,160,17a,21-tetrahydroxy-2 methyl 4pregnene-3-one, removing the 2-ethoxyoxalyl radical therefrom underalkaline conditions to form 20-ethylenedioxy-11B,16a,17a,21-tetrahydroxy-2u-methy1 4 pregnene-3- one, andsubsequently subjecting 20-ethylenedioxy-11B,-16a,17a,21tetrahydroxy-2u-methyl-4-pregnene 3 one to acid hydrolysis.

8. A method of preparing alkali metal enolates of 2-ethoxyoxalyl-ZO-ethylenedioxy-1 1 3,1611, 17u-trihydroxy 4-pregnene-S-ones, which comprises reacting a 21-loweralkanoyloxy-ZO-ethylenedioxy-l1B,16a,17o-trihydroxy 4- pregnene-3-onewith diethyl oxalate in the presence of an alkali metal alkoxide in asolvent.

9. A method of preparing 2-ethoxyoxalyl-ZO-ethylenedi0Xy11/3,16oc,17a,21tetrahydroxy-Zmethyl-4-pregnene- 3-one, which comprises treating analkali metal enolate of 2-ethoxyoxalyl-20-ethylenedioxy-1 1,3,17a,21-tetrahydroxy-4-pregnene-3-one with methyl iodide under alkalineconditions.

10. A method of preparing 20-ethylenedioxy-1 15,1611, :,21tetrahydroxy-2a-methyl-4-pregnene-3one, which comprises removing theZ-ethoxyoxalyl radical from 2- ethoxyoxalyl-2O ethylenedioxy11B,16a,17oc,21 tetrahydroxy-2-methyl-4-pregnene-3one under alkalineconditions.

11. A method of preparingl1fl,16a,17a,21-tetrahydroxy-2a-methyl-4-pregnene-3,20-dione, whichcomprises subjecting ZO-ethylenedioxy-l 1p, 16a,17u,21-tetrahydroxy-2a-methyl-4-pregnene-3-one to acid hydrolysis.

12. A method of preparing a 160:,21-di loweralkanoyloxy-l15,17a-dihydroxy-Za-methyl-4-pregnene-3,20 dione,

7 oxy-l7m-hydroxy-2a-methyl-4 pregnene 3,11,20 trione, which comprisesoxidizing a 160:,21-di lower alkanoyloxy- 11B,17a-dihydroxy-2u-methyl-4-pregnene-3,20-dione.

14. The method of claim 6 to prepare 16a,21-di acetoxy- 1 113,17a-dihydmxy-Za-methyl-4-pregnene-3 ,20- dione.

15. The method of claim 12 to prepare 1611,21-(liacetoxy-l 1B,l7a-dihydroxy-2a-methy1-4-pregnene-3,20-dione.

16. The method of claim 5 to prepare160:,21-diacetoxy-17a-hydroxy-2a-methy1-4- pregnene 3,11,20 trione. i

17. The method of claim 13 to prepare16a,2l-diacetoxy-l7a-hydroxy-2a-methyl-4- pregnene 3,11,20 trione.

' No references cited.

1. A COMPOUND OF THE GROUP HAVING THE GENERAL FROMULA